Hypogonadotropic Hypogonadism 6 With Or Without Anosmia

A number sign (#) is used with this entry because autosomal dominant hypogonadotropic hypogonadism-6 with or without anosmia (HH6) is caused by heterozygous mutation in the fibroblast growth factor-8 gene (FGF8; 600483) on chromosome 10q24, sometimes in association with mutation in another gene, e.g., FGFR1 (136350).

Description

Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).'

For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950.

Clinical Features

Trarbach et al. (2010) identified 2 families with hypogonadotropic hypogonadism-6 with or without anosmia. The proband in the first family had HH6 with primary amenorrhea and moderate microsmia. Among the other 4 affected sibs, 2 had hypogonadotropic hypogonadism (a female with primary amenorrhea and a male with micropenis) and 2 females had pubertal delay; all 4 were normosmic. One of the affected sibs also had cleft lip and palate. In the second family, the proband had hypogonadotropic hypogonadism with micropenis, cryptorchidism, and azoospermia. His sister had hypogonadotropic hypogonadism with primary amenorrhea. Both were normosmic.

Molecular Genetics

Using a candidate gene approach, Falardeau et al. (2008) screened the FGF8 gene in 461 unrelated probands with idiopathic hypogonadotropic hypogonadism, including 193 normosmic patients, 237 anosmic patients, and 21 patients with adult-onset IHH. They identified 6 mutations in the FGF8 gene, in 2 familial cases of Kallmann syndrome (600483.0002 and 600483.0005, respectively), 1 familial case of IHH (600483.0004), 2 sporadic cases of IHH (600483.0001 and 600483.0003, respectively) and 1 case of adult-onset IHH (600483.0006). Probands harboring an FGF8 mutation were screened for other loci underlying IHH, and 2 probands with normosmic IHH (see 600483.0003 and 600483.0004, respectively) were found to carry additional mutations in the FGFR1 gene (see 136350.0023-136350.0025, respectively). None of the FGF8 mutations were found in 180 ethnically matched controls. Structural and in vitro biochemical analysis of the FGF8 mutations, all of which were at highly conserved residues, demonstrated loss of function for all 4 FGF8 isoforms in 4 mutations and loss of function for the FGF8 isoforms involved in GnRH neuronal development in 2 mutations.

By sequencing the FGF8 gene in 2 unrelated probands from Brazil with hypogonadotropic hypogonadism-6, one with and one without anosmia, Trarbach et al. (2010) identified different heterozygous nonsense mutations (R127X, 600483.0007 and R129X, 600483.0008). Both patients had a family history of the disorder. Both mutations mapped to the core domain of the protein, affected all 4 FGF8 isoforms, and led to deletion of a large portion of the protein, predicted to result in nonfunctional FGF8 ligands. The mutations were not found in 150 Brazilian control individuals.